This proposal for continuation of ongoing studies of the control of calcium fluxes across cardiac membranes will focus on mechanisms relevant to the pathogenesis and therapy of cardiac arrhythmias and sudden death. Our overall strategy is to examine effects of possible pathogenic mechanisms on biochemical and biophysical properties of cardiac membranes in vitro and electrophysiological properties of the cardiac sarcolemma, and to define the relation of these pathogenic mechanisms to the mechanisms of action of antiarrhythmic drugs. Effects of fatty acids and fatty acid derivatives, which have been reported to accumulate in and around cells of the ischemic heart, and of changing high energy phosphate levels on ion fluxes will be examined. We will study calcium fluxes in sarcoplasmic reticulum vesicles (SR) and sarcolemmal preparations (SL) in vitro and by electrophysiological studies of ventricular myocardium. Effects of membrane stabilizing (antiarrhythmic) drugs and calcium channel blockers will also be studied in these preparations. Unidirectional calcium fluxes, the reaction mechanism of the calcium pump ATPase protein, and membrane structure will be examined in SR, and the responses of voltage- and time-dependent properties of fast and slow channels to these interventions will be investigated. Identification of possible pathogenic mechanisms and their capacity to be modified by antiarrhythmic drug therapy may aid in the development of means to treat cardiac arrhythmias and prevent sudden death in man.